Interleukin-1 and interleukin-1 receptor antagonist

Cytokines are produced in disease or during immunologic challenge. Some cytokines increase host resistance to disease whereas others trigger inflammatory processes. Interleukin 1 (IL-1) and tumor necrosis factor (TNF) are pro-inflammatory cytokines that affect nearly every cell either alone or in a synergistic fashion. In animal models of infectious, inflammatory or metastatic disease, the role of IL-1 and TNF has been defined by specifically blocking these cytokines. For TNF, anti-TNF monoclonal antibodies and soluble receptors reduce inflammation and lethality. Antibodies to type I IL receptor, IL-1 receptor antagonist (IL-1ra), and soluble IL-1 receptor have been used to reduce the severity of disease in various animal models of local and systemic inflammation. In a Phase III trial, IL-1ra reduced mortality rate in patients with septic shock syndrome by 22%. IL-1ra and soluble receptors to TNF are produced naturally and are elevated in the circulation in several diseases. It is unclear whether these endogenous levels are sufficient to block IL-1 and TNF from triggering their respective cell-bound receptors in disease. IL-1 infusions into patients induce circulating levels of IL-1ra but not IL-1. TNF infusions into patients also induce high levels of soluble TNF receptors.